Skin lightening agents, compositions and methods

ABSTRACT

Cosmetic methods of skin lightening using coumarin derivatives of formula I as skin lightening agents alone or in combination with other skin benefit agents and together with a cosmetic vehicle:  
                 
 
     Where each or both R 1  and/or R 2  represents hydrogen; linear or branched C 1 -C 18  alkyl, alkenyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, hydroxyalkenyl, acyl, cycloacyl, or alkoxy groups;  
     Each or both R 3  and/or R 4 , which may be connected by a single or double carbon-carbon bond (shown as a dotted line), represents hydrogen; linear or branched C 1 -C 18  alkyl, alkenyl, alkoxy, cycloalkyl, or cycloalkenyl group; and  
     Each or both R 5  and/or R 6  represents a hydrogen atom, OH, C 1 -C 4  acyl group, C 1 -C 4  alkyl group, O—CO—R 7 , O—COO—R 8  group, mesyl group or tosyl group, where each or both R 7  and/or R 8  represents hydrogen; linear or branched C 1 -C 18  alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, acyl, cycloacyl, or alkoxy groups.

FIELD OF THE INVENTION

[0001] The invention relates to cosmetic methods of using coumarinderived compounds and cosmetic compositions including same, and morespecifically, coumarin derived resorcinol derivatives, as skinlightening agents.

BACKGROUND OF THE INVENTION

[0002] Many people are concerned with the degree of pigmentation oftheir skin. For example, people with age spots or freckles may wish suchpigmented spots to be less pronounced. Others may wish to reduce theskin darkening caused by exposure to sunlight or to lighten theirnatural skin color. To meet this need, many attempts have been made todevelop products that reduce the pigment production in the melanocytes.However, the substances identified thus far tend to have either lowefficacy or undesirable side effects, such as, for example, toxicity orskin irritation. Therefore, there is a continuing need for new skinlightening agents, with improved overall effectiveness.

[0003] Resorcinol derivatives have cosmetic skin and hair benefits.Certain resorcinol derivatives, particularly 4-substituted resorcinolderivatives, are useful in cosmetic compositions for skin lighteningbenefits. Resorcinol derivatives are described in many publications,including Hu et al., U.S. Pat. No. 6,132,740 and European PatentApplication EP 1 134 207; and Japanese published patent applications JP2001-010925 and JP2000-327557. Resorcinol derivatives are knowncompounds and can be readily obtained by various means, including by amethod wherein a saturated carboxylic acid and resorcinol are condensedin the presence of zinc chloride and the resultant condensate is reducedwith zinc amalgam/hydrochloric acid (Lille, et al., Tr. Nauch-Issled.Inst. Slantsev 1969, No. 18:127-134), or by a method wherein resorcinoland a corresponding alkyl alcohol are reacted in the presence of analumina catalyst at a high temperature of from 200 to 400° C. (BritishPatent No. 1,581,428). Some of these compounds can be irritating to theskin.

[0004] Applicants have now discovered that the use of compounds thatwhich may be derived from coumarin derivatives (although not limited tosuch process), deliver skin lightening benefits. The general chemicalformulas and structures of these compounds is discussed in more detailherein below. Hydroxy coumarin derived compounds, and especially7-hydroxy-coumarin derived compounds which resemble resorcinolderivatives, have been found to be effective and possibly lessirritating to the skin. These compounds are referred to herein as“coumarin derived resorcinol derivatives.”

[0005] Aminophenol derivatives have been described as opticalbrighteners in, for example, Chevalier et al., U.S. Pat. No. 6,403,065.Wella AG, German Patent Application DE 20110355 relates to preparationof (dihydroxyphenyl)acrylamide derivatives and compositions containinghair coloring agents. However, coumarin derived resorcinol derivativesof the present invention have not been used for lightening skin.

SUMMARY OF THE INVENTION

[0006] The use of compounds of the general formula I, and compositionsincluding same, delivers skin lightening benefits with potential reducedirritation. The present invention provides a cosmetic method of skinlightening using a composition comprising in addition to a cosmeticallyacceptable vehicle, about 0.000001 to about 50% of a compound of formulaI,

[0007] Where each or both R₁ and/or R₂ represents hydrogen; linear orbranched C₁-C₁₈ alkyl, alkenyl, cycloalkyl, cycloalkenyl, hydroxyalkyl,hydroxyalkenyl, acyl, cycloacyl, or alkoxy groups. Preferably, one of R₁or R₂ represents hydrogen and the other of R₁ or R₂ represents an alkoxygroup; more preferably, the alkoxy group is CH₂CH₂OMe or CH₂CH₂CH₂OMe;and

[0008] Each or both R₃ and/or R₄ which may be connected by a single ordouble carbon-carbon bond (shown as a dotted line), represents hydrogen;linear or branched C₁-C₁₈ alkyl, alkenyl, alkoxy, cycloalkyl, orcycloalkenyl group. Preferably, R₃ and R₄ are connected by a doublecarbon-carbon bond, and both represent hydrogen; and

[0009] R₅ and/or R₆ may be positioned at the 1-, 2-, 3-, 5-, and/or6-positions on the phenyl ring. Each or both R₅ and/or R₆ represents ahydrogen atom, OH, C₁-C₄ acyl group, C₁-C₄ alkyl group, O—CO—R₇,O—COO—R₈ group, mesyl group or tosyl group, where each or both R₇ and/orR₈ represents hydrogen; linear or branched C₁-C₁₈ alkyl, alkenyl,hydroxyalkyl, hydroxyalkenyl, acyl, cycloacyl, or alkoxy groups. In apreferred embodiment, each or both R₅ and/or R₆ represents OH. In a morepreferred embodiment, both R₅ and R₆ represent OH. This more preferredembodiment, referred to herein as 7-hydroxy-coumarin derivatives, orcoumarin derived resorcinol derivatives, may be prepared by reaction ofmethylamine with 7-hydroxy-coumarin, by a method known in the art. Thehydroxy groups (R₅ and R₆), as well as the R₃ and R₄ groups may befurther substituted by methods known in the art.

[0010] Further skin benefit agents may be included in the compositionsuseful for the inventive method. Organic and inorganic sunscreens mayalso be included.

[0011] The inventive compositions and methods have effective skinlightening properties, may be less irritating to the skin, and arecost-effective.

DETAILED DESCRIPTION OF THE INVENTION

[0012] As used herein, the term “cosmetic composition” is intended todescribe compositions for topical application to human skin.

[0013] The term “skin” as used herein includes the skin on the face,neck, chest, back, arms, axilla, hands, legs, and scalp.

[0014] Except in the examples, or where otherwise explicitly indicated,all numbers in this description indicating amounts of material orconditions of reaction, physical properties of materials and/or use areto be understood as modified by the word “about”. All amounts are byweight of the composition, unless otherwise specified.

[0015] It should be noted that in specifying any range of concentration,any particular upper concentration can be associated with any particularlower concentration.

[0016] For the avoidance of doubt the word “comprising” is intended tomean including but not necessarily consisting of or composed of. Inother words the listed steps or options need not be exhaustive.

[0017] Skin Lightening Agents

[0018] The invention is concerned with the use of compounds of generalformula I, shown below, and compositions including same, as skinlightening agents. A particular advantage of the inventive compositionsand methods is that compounds of general formula I can be lessirritating to the skin than skin lightening compounds with similarstructure, such as 4-substituted resorcinol derivatives:

[0019] Each or both R₁ and/or R₂ represents hydrogen; linear or branchedC₁-C₁₈ alkyl, alkenyl, cycloalkyl, cycloalkenyl, hydroxyalkyl,hydroxyalkenyl, acyl; cycloacyl, or alkoxy groups. Preferably, one of R₁or R₂ represents hydrogen and the other of R₁ or R₂ represents an alkoxygroup; more preferably, the alkoxy group is CH₂CH₂OMe or CH₂CH₂CH₂OMe.

[0020] Each or both R₃ and/or R₄, which may be connected by a single ordouble carbon-carbon bond (shown as a dotted line), represents hydrogen;linear or branched C₁-C₁₈ alkyl, alkenyl, alkoxy, cycloalkyl, orcycloalkenyl group. Preferably, R₃ and R₄ are connected by a doublecarbon-carbon bond, and both represent hydrogen.

[0021] R₅ and/or R₆ may be positioned at the 1-, 2-, 3-, 5-, and/or6-positions on the phenyl ring, and this is denoted in the structure ofthe compound of formula I by elongated lines generally positioned in thephenyl ring but not attached to any of these particular positions on thephenyl ring. Each or both R₅ and/or R₆ represents a hydrogen atom, OH,C1-C4 acyl group, C1-C4 alkyl group, O—CO—R₇ O—COO—R₈ group, mesyl groupor tosyl group, where each or both R₇ and/or R₈ represents hydrogen;linear or branched C₁-C₁₈ alkyl or alkenyl; hydroxyalkyl;hydroxyalkenyl; acyl; cycloacyl; or alkoxy groups. In a preferredembodiment, each or both R₅ and/or R₆ represents OH. In a more preferredembodiment, both R₅ and R₆ represent OH.

[0022] In a most preferred embodiment, both R₅ and R₆ represent OH andare at the 1- and 3-positions, shown as compound of formula II, where R₃and R₄ are both hydrogen and are connected by a double carbon-carbonbond. This most preferred embodiment, referred to herein as7-hydroxy-coumarin derivatives, or coumarin derived resorcinolderivatives, may be prepared by reaction of methylamine (MeNH₂) with7-hydroxy-coumarin, by a method known in the art. Other methods ofderiving compound of formula II may also be available and the inventionis not limited by the method of preparation. The hydroxy groups (R₅ andR₆), as well as the R₁ and R₂ groups may be further substituted bymethods known in the art, to arrive at variations of this compound, asdescribed generally with reference to compounds of formula I.

[0023] The compositions generally contain about 0.000001 to about 50% ofcoumarin derived compounds of general formula I. Compounds of formula IIare preferred. The amount of the coumarin derivative is preferably inthe range of about 0.00001% to about 10%, more preferably about 0.001 toabout 7%, most preferably from 0.01 to about 5%, of the total amount ofa cosmetic composition.

[0024] Optional Skin Benefit Agents

[0025] Preferred cosmetic compositions are those suitable for theapplication to human skin according to the method of the presentinvention, which optionally, but preferably, include a skin benefitagent in addition to a coumarin derivative.

[0026] Suitable additional skin benefit agents include anti-aging,wrinkle-reducing, skin whitening, anti-acne, and sebum reduction agents.Examples of these include alpha-hydroxy acids, beta-hydroxy acids,polyhydroxy acids, hydroquinone, t-butyl hydroquinone, Vitamic Cderivatives, dioic acids, retinoids, and resorcinol derivatives.

[0027] Cosmetically Acceptable Carrier

[0028] The cosmetically acceptable vehicle may act as a dilutant,dispersant or carrier for the skin benefit ingredients in thecomposition, so as to facilitate their distribution when the compositionis applied to the skin.

[0029] The vehicle may be aqueous, anhydrous or an emulsion. Preferably,the compositions are aqueous or an emulsion, especially water-in-oil oroil-in-water emulsion, preferentially oil in water emulsion. Water whenpresent will be in amounts which may range from 5 to 99%, preferablyfrom 20 to 70%, optimally between 40 and 70% by weight.

[0030] Besides water, relatively volatile solvents may also serve ascarriers within compositions of the present invention. Most preferredare monohydric C₁-C₃ alkanols. These include ethyl alcohol, methylalcohol and isopropyl alcohol. The amount of monohydric alkanol mayrange from 1 to 70%, preferably from 10 to 50%, optimally between 15 to40% by weight.

[0031] Emollient materials may also serve as cosmetically acceptablecarriers. These may be in the form of silicone oils and syntheticesters. Amounts of the emollients may range anywhere from 0.1 to 50%,preferably between 1 and 20% by weight.

[0032] Silicone oils may be divided into the volatile and non-volatilevariety. The term “volatile” as used herein refers to those materialswhich have a measurable vapor pressure at ambient temperature. Volatilesilicone oils are preferably chosen from cyclic or linearpolydimethylsiloxanes containing from 3 to 9, preferably from 4 to 5,silicon atoms. Linear volatile silicone materials generally haveviscosities less than about 5 centistokes at 25° C. while cyclicmaterials typically have viscosities of less than about 10 centistokes.Nonvolatile silicone oils useful as an emollient material includepolyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxanecopolymers. The essentially non-volatile polyalkyl siloxanes usefulherein include, for example, polydimethyl siloxanes with viscosities offrom about 5 to about 25 million centistokes at 25° C. Among thepreferred non-volatile emollients useful in the present compositions arethe polydimethyl siloxanes having viscosities from about 10 to about 400centistokes at 25° C.

[0033] Among the ester emollients are:

[0034] (1) Alkenyl or alkyl esters of fatty acids having 10 to 20 carbonatoms. Examples thereof include isoarachidyl neopentanoate, isononylisonanonoate, oleyl myristate, oleyl stearate, and oleyl oleate.

[0035] (2) Ether-esters such as fatty acid esters of ethoxylated fattyalcohols.

[0036] (3) Polyhydric alcohol esters. Ethylene glycol mono and di-fattyacid esters, diethylene glycol mono- and di-fatty acid esters,polyethylene glycol (200-6000) mono- and di-fatty acid esters, propyleneglycol mono- and di-fatty acid esters, polypropylene glycol 2000monooleate, polypropylene glycol 2000 monostearate, ethoxylatedpropylene glycol monostearate, glyceryl mono- and di-fatty acid esters,polyglycerol poly-fatty esters, ethoxylated glyceryl mono-stearate,1,3-butylene glycol monostearate, 1,3-butylene glycol distearate,polyoxyethylene polyol fatty acid ester, sorbitan fatty acid esters, andpolyoxyethylene sorbitan fatty acid esters are satisfactory polyhydricalcohol esters.

[0037] (4) Wax esters such as beeswax, spermaceti, myristyl myristate,stearyl stearate and arachidyl behenate.

[0038] (5) Sterols esters, of which cholesterol fatty acid esters areexamples thereof.

[0039] Fatty acids having from 10 to 30 carbon atoms may also beincluded as cosmetically acceptable carriers for compositions of thisinvention. Illustrative of this category are pelargonic, lauric,myristic, palmitic, stearic, isostearic, hydroxystearic, oleic,linoleic, ricinoleic, arachidic, behenic and erucic acids.

[0040] Humectants of the polyhydric alcohol-type may also be employed ascosmetically acceptable carriers in compositions of this invention. Thehumectant aids in increasing the effectiveness of the emollient, reducesscaling, stimulates removal of built-up scale and improves skin feel.Typical polyhydric alcohols include glycerol, polyalkylene glycols andmore preferably alkylene polyols and their derivatives, includingpropylene glycol, dipropylene glycol, polypropylene glycol, polyethyleneglycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol,hexylene glycol, 1,3-butylene glycol, 1,2,6-hexanetriol, ethoxylatedglycerol, propoxylated glycerol and mixtures thereof. For best resultsthe humectant is preferably propylene glycol or sodium hyaluronate. Theamount of humectant may range anywhere from 0.5 to 30%, preferablybetween 1 and 15% by weight of the composition.

[0041] Thickeners may also be utilized as part of the cosmeticallyacceptable carrier of compositions according to the present invention.Typical thickeners include crosslinked acrylates (e.g. Carbopol 982),hydrophobically-modified acrylates (e.g. Carbopol 1382), cellulosicderivatives and natural gums. Among useful cellulosic derivatives aresodium carboxymethylcellulose, hydroxypropyl methylcellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose andhydroxymethyl cellulose. Natural gums suitable for the present inventioninclude guar, xanthan, sclerotium, carrageenan, pectin and combinationsof these gums. Amounts of the thickener may range from 0.0001 to 5%,usually from 0.001 to 1%, optimally from 0.01 to 0.5% by weight.

[0042] Collectively the water, solvents, silicones, esters, fatty acids,humectants and/or thickeners will constitute the cosmetically acceptablecarrier in amounts from 1 to 99.9%, preferably from 80 to 99% by weight.

[0043] An oil or oily material may be present, together with anemulsifier to provide either a water-in-oil emulsion or an oil-in-wateremulsion, depending largely on the average hydrophilic-lipophilicbalance (HLB) of the emulsifier employed.

[0044] Surfactants may also be present in cosmetic compositions of thepresent invention. Total concentration of the surfactant will range from0.1 to 40%, preferably from 1 to 20%, optimally from 1 to 5% by weightof the composition. The surfactant may be selected from the groupconsisting of anionic, nonionic, cationic and amphoteric actives.Particularly preferred nonionic surfactants are those with a C₁₀-C₂₀fatty alcohol or acid hydrophobe condensed with from 2 to 100 moles ofethylene oxide or propylene oxide per mole of hydrophobe; C₂-C₁₀ alkylphenols condensed with from 2 to 20 moles of alkylene oxide; mono- anddi-fatty acid esters of ethylene glycol; fatty acid monoglyceride;sorbitan, mono- and di-C₈-C₂₀ fatty acids; block copolymers (ethyleneoxide/propylene oxide); and polyoxyethylene sorbitan as well ascombinations thereof. Alkyl polyglycosides and saccharide fatty amides(e.g. methyl gluconamides) are also suitable nonionic surfactants.

[0045] Preferred anionic surfactants include soap, alkyl ether sulfateand sulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates,alkyl and dialkyl sulfosuccinates, C₈-C₂₀ acyl isethionates, acylglutamates, C₈-C₂₀ alkyl ether phosphates and combinations thereof.

[0046] Optional Components

[0047] In the cosmetic compositions of the invention, there may be addedvarious medically effective ingredients, such as allantoin, a placentaextract; other thickeners, plasticizers; calamine; pigments;antioxidants; chelating agents; and perfumes; as well as additionalsunscreens such organic sunscreens, typical of which are PARSOL 1789 andPARSOL MCX.

[0048] Other adjunct minor components may also be incorporated into thecosmetic compositions. These ingredients may include coloring agents,opacifiers, and perfumes. Amounts of these other adjunct minorcomponents may range anywhere from 0.001% up to 20% by weight of thecomposition.

[0049] Sunscreens

[0050] For use as sunscreen, metal oxides may be used alone or inmixture and/or in combination with organic sunscreens. Examples oforganic sunscreens include but are not limited those set forth in thetable below: TABLE 3 CTFA Name Trade Name Supplier Benzophenone-3 UVINULM-40 BASF Chemical Co. Benzophenone-4 UVINUL MS-40 BASF Chemical Co.Benzophenone-8 SPECRA-SORB American Cyanamide UV-24 DEA MethoxycinnamateBERNEL HYDRO Bernel Chemical Ethyl dihydroxypropyl- AMERSCREEN PAmerchol Corp. PABA Glyceryl PABA NIPA G.M.P.A. Nipa Labs. HomosalateKEMESTER HMS Hunko Chemical Methyl anthranilate SUNAROME UVA FeltonWorldwide Octocrylene UVINUL N-539 BASF Chemical Co. Octyl dimethyl PABAAMERSCOL Amerchol Corp. Octyl methoxycinnamate PARSOL MCX BernelChemical Octyl salicylate SUNAROME WMO Felton Worldwide PABA PABANational Starch 2-Phenylbenzimidazole- EUSOLEX 232 EM Industries5-sulphonic acid TEA salicylate SUNAROME W Felton Worldwide3-(4-methylbenzylidene)- EUSOLEX 6300 EM Industries camphorBenzophenone-1 UVINUL 400 BASF Chemical Co. Benzophenone-2 UVINUL D-50BASF Chemical Co. Benzophenone-6 UVINUL D-49 BASF Chemical Co.Benzophenone-12 UVINUL 408 BASF Chemical Co. 4-Isopropyl dibenzoylEUSOLEX 8020 EM Industries methane Butyl methoxy dibenzoyl PARSOL 1789Givaudan Corp. methane Etocrylene UVINUL N-35 BASF Chemical Co.

[0051] The amount of the organic sunscreens in the cosmetic compositionis preferably in the range of about 0.1 wt % to about 10 wt %, morepreferably about 1 wt % to 5 wt %.

[0052] Preferred organic sunscreens are PARSOL MCX and Parsol 1789, dueto their effectiveness and commercial availability.

[0053] Use of the Composition

[0054] The method according to the invention is intended primarily asusing a personal care product for topical application to human skin, aswell as to protect exposed skin from the harmful effects of excessiveexposure to sunlight.

[0055] In use, a small quantity of the composition, for example from 1to 5 ml, is applied to exposed areas of the skin, from a suitablecontainer or applicator and, if necessary, it is then spread over and/orrubbed into the skin using the hand or fingers or a suitable device.

[0056] Product Form and Packaging

[0057] The cosmetic composition useful for the method of the inventioncan be formulated as a lotion having a viscosity of from 4,000 to 10,000mPas, a fluid cream having a viscosity of from 10,000 to 20,000 mPas ora cream having a viscosity of from 20,000 to 100,000 mPas, or above. Thecomposition can be packaged in a suitable container to suit itsviscosity and intended use by the consumer. For example, a lotion orfluid cream can be packaged in a bottle or a roll-ball applicator or apropellant-driven aerosol device or a container fitted with a pumpsuitable for finger operation. When the composition is a cream, it cansimply be stored in a non-deformable bottle or squeeze container, suchas a tube or a lidded jar. When the composition is a solid or semi-solidstick, it may be packaged in a suitable container for manually ormechanically pushing out or extruding the composition.

[0058] The invention accordingly also provides a closed containercontaining a cosmetically acceptable composition as herein defined.

[0059] The following examples are by way of example, not by way oflimitation, of the principles of the present invention, to illustratethe best mode of carrying out the invention.

EXAMPLE 1

[0060] The following compounds were used throughout the examples thatfollow. These compounds were prepared in accordance with the proceduresset forth in this Example 1.

[0061] The compound of formula A, referred to herein as 7-hydroxycoumarin was used as a starting material to prepare the coumarin derivedresorcinol compounds according to the present invention.

[0062] Synthesis of Resorcinol Amide 1

[0063] The compound of formula III is referred to herein ResorcinolAmide 1. To prepare resorcinol amide 1, 7-hydroxycoumarin (8.1 g; 0.05mole; from Sigma-Aldrich, Milwaukee, Wis.) was dissolved in methanol (50ml) and methyl amine was bubbled through the reaction. After 48 hrs, gaschromatography analysis showed the disappearance of 7-hydroxycoumarin.Methanol/methyl-amine was removed on a rotavap and the crude product waschromatographed on a silica column to give the resorcinol amide 1 in 75%isolated yield. The structure of this chemical was confirmed by Massspectroscopy, NMR (H1 and C13) and Infrared.

[0064] Synthesis of Resorcinol Amide 2

[0065] The compound of formula IV is referred to herein as ResorcinolAmide 2. To prepare resorcinol amide 2, 7-hydroxycoumarin (16.2 g; 0.1mole;) was dissolved in 2-methoxyethylamine (75.1 g; 1.0 mole, fromAldrich, Milwaukee, Wis.) and stirred at room temperature. After 24 hrs,gas chromatography analysis showed the disappearance of7-hydroxycoumarin. The excess 2-methoxyethylamine was removed on arotavap and the crude product was chromatographed on a silica column, togive the resorcinol amide 2 in 89% isolated yield. The structure of thischemical was confirmed by Mass spectroscopy, NMR (H1 and C13) andInfrared.

EXAMPLE 2

[0066] Cosmetic compositions within the scope of the invention wereprepared.

[0067] A base formulation shown in Table 3, below, was made by heatingphase A ingredients to 70 to 85° C. with stirring. Phase B ingredientswere heated in a separate container to 70 to 85° C. with stirring. Then,phase A was added into phase B while both phases were kept at 70 to 85°C. The mixture was stirred for at least 15 minutes at 70 to 85° C., thencooled.

[0068] A base formulation is shown in the table below. TABLE 4 3a 3bIngredients % wt. % wt. Phase Isostearyl Palmitate 6.00 6.00 A C12-C15Alkyl Octanoate 3.00 3.00 A PEG-100 Stearate 2.00 2.00 A GlycerylHydroxystearate 1.50 1.50 A Stearyl Alcohol 1.50 1.50 A Stearic acid3.00 4.00 A TEA, 99% 1.20 1.20 B Dimethicone 1.00 1.00 A SorbitanMonostearate 1.00 1.00 A Magnesium Aluminum Silicate 0.60 0.60 B VitaminE acetate 0.10 0.10 A Cholesterol 0.50 0.50 A Simethicone 0.01 0.01 BXanthan gum 0.20 0.20 B Hydroxyethylcellulose 0.50 0.50 B Propylparaben0.10 0.10 B Disodium EDTA 0.05 0.05 B Butylated hydroxytolene 0.05 0.05B Resorcinol Amide 1 0.05 2.00 B Niacinamide 1.00 1.00 B Metal oxide2.50 5.00 B Methylparaben 0.15 0.15 B Water BAL* BAL* B Total 100.00100.00 B

EXAMPLE 3

[0069] Additional cosmetic compositions within the scope of theinvention were prepared. TABLE 5 Wt % Phase water, DI BALANCE A disodiumEDTA  0.05 A magnesium aluminum silicate 0.6 A methyl paraben  0.15 Asimethicone  0.01 A butylene glycol 1,3 3.0 A hydroxyethylcellulose 0.5A glycerine, USP 2.0 A xanthan gum 0.2 A triethanolamine 1.2 B stearicacid 3.0 B propyl paraben NF 0.1 B glyceryl hydroxystearate 1.5 Bstearyl alcohol 1.5 B isostearyl palmitate 6.0 B C12-15 alcoholsoctanoate 3.0 B dimethicone 1.0 B cholesterol NF 0.5 B sorbitan stearate1.0 B Micronized titanium dioxide 5.0 C tocopheryl acetate 0.1 B PEG-100stearate 2.0 B sodium stearoyl lactylate 0.5 B hydroxycaprylic acid 0.1C Resorcinol Amide 2 10.0  C PARSOL MCX 2.4 C alpha-bisabolol 0.2 C

[0070] The composition of Example 3, was prepared as follows:

[0071] 1. Heat Phase A to 80° C.

[0072] 2. Heat Phase B to 75° C. in a separate container

[0073] 3. Add B to A and mix with heat off for 30 min.

[0074] 4. At 50° C. add Phase C and mix for 10 min.

EXAMPLES 4-11

[0075] A set of additional compositions useful in the methods of thepresent invention were prepared within the scope of the presentinvention and are listed in the table below. TABLE 6 Examples (wt. %) 3acid soap Ingredients Phase base 4 5 6 7 8 9 10 Stearic acid A 17.9 17.917.9 17.9 17.9 17.9 17.9 17.9 Sodium cetearyl A 2.21 1 1.5 2 3 2sulfate* (emulsifier) Myrj 59* A 2 2 2 2 2 1 (emulsifier) Span 60* A 2 22 2 2 1 (emulsifiers) Resorcinol Amide 1 B 0.05 0.05 2.0 2.0 3.5 3.5 5.010.0 Micronized Zinc B 2.50 5.00 5.00 2.50 2.50 5.00 2.50 5.00 OxideKOH, 22% (form in 2.20 situ soap with stearic acid Octyl 2.50 2.50 2.502.50 methoxycinnamate Water B BAL BAL BAL BAL BAL BAL BAL Glycerin B 1 11 1 1 1 1 1

EXAMPLE 12

[0076] This example shows the skin lightening effect of using7-hydroxy-coumarin derived resorcinol compounds as skin lighteningagents in accordance with the inventive method. This experiment wascarried out using a cell based assay.

[0077] B16 mouse melanoma cells were utilized in the followingexperiment to evaluate the efficacy of skin lightening agents. B16 cellswere plated in 96-well microtiter plates at a density of 5000 cells perwell and cultured overnight in Dulbecco's Modified Eagle's Medium(phenol red free) containing 10% fetal bovine serum and 1%penicillin/streptomycin at 37° C. in the presence of 5% CO₂. After 24hours, the medium was replaced with fresh growth medium containing thetreatments. All cultures were incubated for 72 hours at which timemelanin was visible in the control treatment. The melanin-containingmedium was transferred to a clean 96-well plate and quantified byreading the absorbency at 530-nm. Cell viability was assessed bymeasurement of lactate dehydrogenase levels to ensure the decrease inmelanin was not a result of cellular toxicity. TABLE 7 % of ControlCompound Concentration (Melanin Synthesis) 4-Ethyl Resorcinol 6.25micromolar 15.6% Resorcinol Amide 1 6.25 micromolar 13.1% ResorcinolAmide 2 6.25 micromolar 13.7%

[0078] From the results tabulated above it appears that coumarin derivedresorcinol compounds of the present invention reduce melanin synthesisto about the same or better degree than 4-ethyl resorcinol.

EXAMPLE 13 Mushroom Tyrosinase Assay

[0079] Mushroom tyrosinase inhibition is indicative of reduction inmelanin synthesis, thereby showing skin lightening effect. Thisexperiment shows the efficacy of coumarin derived resorcinol derivativesof the present invention.

[0080] Into each well of a 96-well plate, 150 microliters of phosphatebuffer (100 mM, pH 7.0), 10 microliters of L-DOPA (L-3,4-Dihydroxyphenylalanine, 10 mM), and 20 microliters of skin lighteningagent (dissolved in ethanol, which is the control) were added. Followingan initial measurement of background absorbency at 475-nm, 20microliters of mushroom tyrosinase (Sigma T-7755; 6050 units/ml) wasadded and incubated at room temperature.

[0081] Absorbency is read at 475-nm over the following time points: 0,2, 4, and 6.5 minutes. The data is plotted as 475-nm absorbency vs. time(minutes) and the slope of the line is calculated (ΔAbs 475 nm/min).Values are expressed as the percentage of the respective untreatedethanol control reaction.${\% \quad {of}\quad {Control}} = {\frac{\left( {{Reaction}\quad {rate}\quad {for}\quad {treated}\quad {reaction}} \right)}{\left( {{Reaction}\quad {rate}\quad {for}\quad {untreated}{\quad \quad}{control}} \right)} \times 100\quad \%}$

TABLE 8 % of Control Compound Concentration (Melanin Synthesis) 4-EthylResorcinol 0.1 uM 72.7 1 uM 46.3 10 uM 30.8 100 uM 20.7 7-HydroxyCoumarin 0.1 uM 104 1 uM 100 10 uM 108 100 uM 117 Resorcinol Amide 1 0.1uM 75.1 1 uM 51.0 10 uM 53.0 100 uM 53.4 Resorcinol Amide 2 0.1 uM 84.21 uM 59.5 10 uM 58.0 100 uM 57.9

[0082] The data show that the hydrolyzed coumarin amide is substantiallyas effective as 4-ethyl resorcinol, both compounds having good skinlightening effects. The 7-hydroxy coumarin compound from which thecompounds of the present invention may be derived is effective in skinlightening.

[0083] It should be understood that the specific forms of the inventionherein illustrated and described are intended to be representative only.Changes, including but not limited to those suggested in thisspecification, may be made in the illustrated embodiments withoutdeparting from the clear teachings of the disclosure. Accordingly,reference should be made to the following appended claims in determiningthe full scope of the invention.

What is claimed is:
 1. A cosmetic method of skin lightening comprisingapplying to the skin a composition comprising: a. about 0.000001 toabout 50% of a compound of general formula I

Wherein each or both R₁ and/or R₂ is selected from the group consistingof hydrogen; linear or branched C₁-C₁₈ alkyl, alkenyl, cycloalkyl,cycloalkenyl, hydroxyalkyl; hydroxyalkenyl, acyl; cycloacyl, and alkoxygroups; Wherein each or both R₃ and/or R₄, is selected from the groupconsisting of hydrogen; linear or branched C₁-C₁₈ alkyl, alkenyl,alkoxy, cycloalkyl, and cycloalkenyl group; wherein the dotted line is asingle or double carbon-carbon bond; Wherein each or both R₅ and/or R₆is selected from the group consisting of a hydrogen atom, OH, C₁-C₄ acylgroup, C₁-C₄ alkyl group, O—CO—R₇, or O—COO—R₈ group; wherein each orboth R₇ and/or R₈ is selected from the group consisting of hydrogen;linear or branched C₁-C₁₈ alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl,acyl, cycloacyl, or alkoxy groups; wherein R₅ and/or R₆ may bepositioned at the 1-, 2-, 3-, 5-, and/or 6-positions on the phenyl ring;and b. a cosmetically acceptable carrier.
 2. The method of claim 1,wherein said composition further comprises a sunscreen.
 3. The method ofclaim 2, wherein said sunscreen is a micronized metal oxide.
 4. Themethod of claim 1, wherein said compound is a hydroxy coumarin derivedresorcinol derivative.
 5. The method of claim 1, wherein said compoundis a compound of general formula II:


6. The cosmetic method of claim 1, wherein R₁ and R₂ both representhydrogen.
 7. The cosmetic method according to claim 1, wherein saidcomposition further comprises a skin benefit agent selected from thegroup consisting of alpha-hydroxy acids, beta-hydroxy acids, polyhydroxyacids, hydroquinone, t-butyl hydroquinone, Vitamin C derivatives, dioicacids, retinoids, resorcinol derivatives, and mixtures thereof.
 8. Thecosmetic method of claim 1, wherein said composition further comprisesan organic sunscreen selected from the group consisting ofBenzophenone-3, Benzophenone-4 , Benzophenone-8, DEA, Methoxycinnamate,Ethyl dihydroxypropyl-PABA, Glyceryl PABA, Homosalate, Methylanthranilate, Octocrylene, Octyl dimethyl PABA, Octyl methoxycinnamate(PARSOL MCX), Octyl salicylate, PABA, 2-Phenylbenzimidazole-5-sulphonicacid, TEA salicylate, 3-(4-methylbenzylidene)-camphor, Benzophenone-1,Benzophenone-2, Benzophenone-6, Benzophenone-12, 4-Isopropyl dibenzoylmethane, Butyl methoxy dibenzoyl methane (PARSOL 1789), Etocrylene, andmixtures thereof.
 9. A cosmetic composition comprising: a. about0.000001 to about 50% of a compound of general formula I

wherein each or both R₁ and/or R₂ is selected from the group consistingof hydrogen; linear or branched C₁-C₁₈ alkyl, alkenyl, cycloalkyl,cycloalkenyl, hydroxyalkyl; hydroxyalkenyl, acyl; cycloacyl, and alkoxygroups; wherein each or both R₃ and/or R₄, is selected from the groupconsisting of hydrogen; linear or branched C₁-C₁₈ alkyl, alkenyl,alkoxy, cycloalkyl, and cycloalkenyl group; wherein the dotted line is asingle or double carbon-carbon bond; wherein each or both R₅ and/or R₆is selected from the group consisting of a hydrogen atom, OH, C₁-C₄ acylgroup, C₁-C₄ alkyl group, O—CO—R₇, or O—COO—R₈ group, wherein each orboth R₇ and/or R₈ is selected from the group consisting of hydrogen;linear or branched C₁-C₁₈ alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl,acyl, cycloacyl, or alkoxy groups; Wherein R₅ and/or R₆ may bepositioned at the 1-, 2-, 3-, 5-, and/or 6-positions on the phenyl ring;and b. a cosmetically acceptable carrier.
 10. The cosmetic compositionof claim 9, wherein said compound is a compound of general formula II:


11. The cosmetic composition of claim 10, wherein R₁ and R₂ bothrepresent hydrogen.
 12. The cosmetic composition of claim 9, whereinsaid compound comprises about 0.00001% to about 10% of said composition.13. The cosmetic composition of claim 9, wherein said compound comprisesabout 0.001% to about 7% of said composition.
 14. The cosmeticcomposition of claim 9, wherein said compound comprises about 0.01% toabout 5% of said composition.